Exploring miRNA-target gene pair detection in disease with coRmiT.

A wide range of approaches can be used to detect micro RNA (miRNA)-target gene pairs (mTPs) from expression data, differing in the ways the gene and miRNA expression profiles are calculated, combined and correlated. However, there is no clear consensus on which is the best approach across all datasets. Here, we have implemented multiple strategies and applied them to three distinct rare disease datasets that comprise smallRNA-Seq and RNA-Seq data obtained from the same samples, obtaining mTPs related to the disease pathology. All datasets were preprocessed using a standardized, freely available computational workflow, DEG_workflow. This workflow includes coRmiT, a method to compare multiple strategies for mTP detection. We used it to investigate the overlap of the detected mTPs with predicted and validated mTPs from 11 different databases. Results show that there is no clear best strategy for mTP detection applicable to all situations. We therefore propose the integration of the results of the different strategies by selecting the one with the highest odds ratio for each miRNA, as the optimal way to integrate the results. We applied this selection-integration method to the datasets and showed it to be robust to changes in the predicted and validated mTP databases. Our findings have important implications for miRNA analysis. coRmiT is implemented as part of the ExpHunterSuite Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite.

Effects of high-intensity training on fatty infiltration in paraspinal muscles in elderly males with osteosarcopenia - the randomized controlled FrOST study.

BACKGROUND: Osteosarcopenia is a common geriatric syndrome with an increasing prevalence with age, leading to secondary diseases and complex consequences such as falls and fractures, as well as higher mortality and frailty rates. There is a great need for prevention and treatment strategies. METHODS: In this analysis, we used magnetic resonance imaging (MRI) data from the randomised controlled FrOST trial, which enrolled community-dwelling osteosarcopenic men aged > 72 years randomly allocated to 16 months of twice-weekly high-intensity resistance training (HIRT) or a non-training control group. MR Dixon imaging was used to quantify the effects of HIRT on muscle fat infiltration in the paraspinal muscles, determined as changes in muscle tissue, fat faction and intermuscular adipose tissue (IMAT) in the erector spinae and psoas major muscles. Intention-to-treat analysis with multiple imputation was used to analyse the data set. RESULTS: After 16 months of intervention, 15 men from the HIRT and 16 men from the CG were included in the MRI analysis. In summary, no positive effects on the fat infiltration of the erector spinae and psoas major muscles were observed. CONCLUSIONS: The previously reported positive effects on lumbar spine bone mineral density (BMD) suggest that mechanotransduction induces tropic effects on bone, but that fat infiltration of the erector spinae and psoas major muscles are either irreversible or, for some unknown reason, resistant to exercise. Because of the beneficial effects on spinal BMD, HIRT is still recommended in osteosarcopenic older men, but further research is needed to confirm appropriate age-specific training exercises for the paraspinal muscles. The potential of different MRI sequences to quantify degenerative and metabolic changes in various muscle groups must be better characterized. TRIAL REGISTRATIONS: FrOST was approved by the University Ethics Committee of the Friedrich-Alexander University of Erlangen-Nürnberg (number 67_15b and 4464b) and the Federal Office for Radiation Projection (BfS, number Z 5-2,246,212 - 2017-002). Furthermore, it fully complies with the Declaration of Helsinki and is registered at ClinicalTrials.gov: NCT03453463 (05/03/2018). JAMA 310:2191-2194, 2013.

Ready-to-use nanopore platform for label-free small molecule quantification: Ethanolamine as first example.

In recent decades, nanopores have become a promising diagnostic tool. Protein and solid-state nanopores are increasingly used for both RNA/DNA sequencing and small molecule detection. The latter is of great importance, as their detection is difficult or expensive using available methods such as HPLC or LC-MS. DNA aptamers are an excellent detection element for sensitive and specific detection of small molecules. Herein, a method for quantifying small molecules using a ready-to-use sequencing platform is described. Taking ethanolamine as an example, a strand displacement assay is developed in which the target-binding aptamer is displaced from the surface of magnetic particles by ethanolamine. Non-displaced aptamer and thus the ethanolamine concentration are detected by the nanopore system and can be quantified in the micromolar range using our in-house developed analysis software. This method is thus the first to describe a label-free approach for the detection of small molecules in a protein nanopore system.

Factors predicting long-term outcomes following physiotherapy in patients with subacromial pain syndrome: a secondary analysis.

BACKGROUND: Although patients with shoulder complaints are frequently referred to physiotherapy, putative predictive factors for outcomes are still unclear. In this regard, only a limited amount of scientific data for patients with subacromial pain syndrome exist, with inconsistent results. An improved knowledge about the ability of baseline variables to predict outcomes could help patients make informed treatment decisions, prevent them from receiving ineffective treatments, and minimize the risk of developing chronic pain. AIM: The aims of this secondary longitudinal analysis are threefold: First, to investigate baseline differences between patients with and without successful long-term outcomes following physiotherapy. Second, to compare the predictive ability of two sets of putative predictive variables on outcomes, one based on the literature and one based on the data of the original trial. Third, to explore the contribution of short-term follow-up data to predictive models. METHODS: Differences between responders and nonresponders were calculated. The predictive ability of variables defined through literature and of variables based on the Akaike Information Criterion (AIC) from the original trial dataset on the Shoulder Pain and Disability Index and the Patients' Global Impression of Change at the one-year follow-up were analyzed. To test the robustness of the results, different statistical models were used. To investigate the contribution of follow-up data to prediction, short-term data were included in the analyses. RESULTS: A sample of 87 patients with subacromial pain syndrome was analyzed. 77% (n = 67) of these participants were classified as responders. Higher expectations and short-term change scores were positive, and higher fear avoidance beliefs, greater baseline disability and pain levels were negative predictors of long-term outcomes in patients with subacromial pain syndrome. CONCLUSIONS: Although our results are in line with previous research and support the use of clinical factors for prediction, our findings suggest that psychological factors, especially patient expectations and fear avoidance beliefs, also contribute to long-term outcomes and should therefore be considered in the clinical context and further research. However, the hypotheses and recommendations generated from our results need to be confirmed in further studies due to their explorative nature. TRIAL REGISTRATION: The original trial was registered at Current Controlled Trials under the trial registration number ISRCTN86900354 on March 17, 2010.

Non-Athletic Cohorts Enrolled in Longitudinal Whole-Body Electromyostimulation Trials-An Evidence Map.

Whole-body electromyostimulation (WB-EMS) can be considered as a time-efficient, joint-friendly, and highly customizable training technology that attracts a wide range of users. The present evidence map aims to provide an overview of different non-athletic cohorts addressed in WB-EMS research. Based on a comprehensive systematic search according to PRISMA, eighty-six eligible longitudinal trials were identified that correspond with our eligibility criteria. In summary, WB-EMS research sufficiently covers all adult age categories in males and females. Most cohorts addressed (58%) were predominately or exclusively overweight/obese, and in about 60% of them, diseases or conditions were inclusion criteria for the trials. Cohorts specifically enrolled in WB-EMS trials suffer from cancer/neoplasm (n = 7), obesity (n = 6), diabetes mellitus (n = 5), metabolic syndrome (n = 2), nervous system diseases (n = 2), chronic heart failure (n = 4), stroke (n = 1), peripheral arterial diseases (n = 2), knee arthrosis (n = 1), sarcopenia (n = 3), chronic unspecific low back pain (n = 4), and osteopenia (n = 3). Chronic kidney disease was an eligibility criterion in five WB-EMS trials. Finally, three studies included only critically ill patients, and two further studies considered frailty as an inclusion criterion. Of importance, no adverse effects of the WB-EMS intervention were reported. In summary, the evidence gaps in WB-EMS research were particular evident for cohorts with diseases of the nervous and cerebrovascular system.

Real-Time Nanopore Q20+ Sequencing Enables Extremely Fast and Accurate Core Genome MLST Typing and Democratizes Access to High-Resolution Bacterial Pathogen Surveillance.

Next-generation whole-genome sequencing is essential for high-resolution surveillance of bacterial pathogens, for example, during outbreak investigations or for source tracking and escape variant analysis. However, current global sequencing and bioinformatic bottlenecks and a long time to result with standard technologies demand new approaches. In this study, we investigated whether novel nanopore Q20+ long-read chemistry enables standardized and easily accessible high-resolution typing combined with core genome multilocus sequence typing (cgMLST). We set high requirements for discriminatory power by using the slowly evolving bacterium Bordetella pertussis as a model pathogen. Our results show that the increased raw read accuracy enables the description of epidemiological scenarios and phylogenetic linkages at the level of gold-standard short reads. The same was true for our variant analysis of vaccine antigens, resistance genes, and virulence factors, demonstrating that nanopore sequencing is a legitimate competitor in the area of next-generation sequencing (NGS)-based high-resolution bacterial typing. Furthermore, we evaluated the parameters for the fastest possible analysis of the data. By combining the optimized processing pipeline with real-time basecalling, we established a workflow that allows for highly accurate and extremely fast high-resolution typing of bacterial pathogens while sequencing is still in progress. Along with advantages such as low costs and portability, the approach suggested here might democratize modern bacterial typing, enabling more efficient infection control globally.

Exercise training and bone mineral density in postmenopausal women: an updated systematic review and meta-analysis of intervention studies with emphasis on potential moderators.

The aim of this systematic review and meta-analysis was (1) to determine exercise effects on bone mineral density (BMD) in postmenopausal women and (2) to address the corresponding implication of bone and menopausal status or supervision in postmenopausal women. A comprehensive search of eight electronic databases according to the PRISMA statement up to August 9, 2022, included controlled exercise trials ≥ 6 months. BMD changes (standardized mean differences: SMD) at the lumbar spine (LS), femoral neck (FN), and total hip (TH) were considered as outcomes. Study group comparisons were conducted for osteopenia/osteoporosis versus normal BMD, early versus late postmenopausal women, and predominantly supervised versus predominantly non-supervised study arms. We applied an inverse heterogeneity (IVhet) model. In summary, 80 studies involving 94 training and 80 control groups with a pooled number of 5581 participants were eligible. The IVhet model determined SMDs of 0.29 (95% CI: 0.16-0.42), 0.27 (95% CI: 0.16-0.39), and 0.41 (95% CI: 0.30-0.52) for LS, FN, and THBMD, respectively. Heterogeneity between the trial results varied from low (I2 = 20%, TH BMD) to substantial (I2 = 68%, LS-BMD). Evidence for publication bias/small study effects was negligibly low (FN-, TH-BMD) to high (LSBMD). We observed no significant differences (p > .09) for exercise effects on LS-, FN-, or TH-BMD-LS between studies/study arms with or without osteopenia/osteoporosis, early versus late postmenopausal women, or predominantly supervised versus non-supervised exercise programs. Using robust statistical methods, the present work provides further evidence for a positive effect of exercise on BMD in postmenopausal women. Differences in bone status (osteopenia/osteoporosis versus normal bone), menopausal status (early versus late postmenopausal), and supervision (yes versus no) did not significantly affect the exercise effects on BMD at LS or proximal femur.

Exercise and the prevention of major osteoporotic fractures in adults: a systematic review and meta-analysis with special emphasis on intensity progression and study duration.

The role of exercise in preventing osteoporotic fractures is vague, and further recommendations for optimized exercise protocols are very rare. In the present work, we provided positive evidence for exercise effects on the number of osteoporotic fractures in adults, albeit without observing any significant relevance of intensity progression or study duration. INTRODUCTION: Osteoporotic fractures are a major challenge confronting our aging society. Exercise might be an efficient agent for reducing osteoporotic fractures in older adults, but the most promising exercise protocol for that purpose has yet to be identified. The present meta-analysis thus aimed to identify important predictors of the exercise effect on osteoporotic fractures in adults. METHODS: We conducted a systematic search of six literature databases according to the PRISMA guideline that included controlled exercise studies and reported the number of low-trauma major osteoporotic fractures separately for exercise (EG) and control (CG) groups. Primary study outcome was incidence ratio (IR) for major osteoporotic fractures. Sub-analyses were conducted for progression of intensity (yes vs. no) during the trial and the study duration (≤ 12 months vs. > 12 months). RESULTS: In summary, 11 studies with a pooled number of 9715 participant-years in the EG and 9592 in the CG were included. The mixed-effects conditional Poisson regression revealed positive exercise effects on major osteoporotic fractures (RR: 0.75, 95% CI: 0.54-0.94, p = .006). Although studies with intensity progression were more favorable, our subgroup analysis did not determine significant differences for diverging intensity progression (p = .133) or study duration (p = .883). Heterogeneity among the trials of the subgroups (I2 ≤ 0-7.1%) was negligible. CONCLUSION: The present systematic review and meta-analysis provided significant evidence for the favorable effect of exercise on major osteoporotic fractures. However, diverging study and exercise characteristics along with the close interaction of exercise parameters prevented the derivation of reliable recommendations for exercise protocols for fracture reductions. PROSPERO ID: CRD42021250467.

Long-term effects of smoking on serum concentrations of oxidative stress biomarkers: Results of a large, population-based cohort study.

INTRODUCTION: Cross-sectional studies have consistently shown an association between current smoking and oxidative stress biomarkers. However, no longitudinal studies have been performed so far. METHODS: The oxidative stress biomarkers "total thiol groups of serum proteins" (TTP), and "derivatives of reactive oxygen metabolites" (D-ROM) were measured in serum samples of 3835 participants of a population-based, German cohort study of older adults (age: 60-84 years) with repeated measurements for 2834 participants three years later. Multivariable linear regression models were applied and ß-coefficients with 95% confidence intervals were obtained. RESULTS: In both cross-sectional and longitudinal analysis, current smoking was statistically significantly associated with increased D-ROM levels, and a dose-response relationship between the amount of daily tobacco consumption and the D-ROM concentrations was observed that plateaued at ≥15 g of tobacco consumption per day. Former smoking was also associated with D-ROM levels. Only former smokers who quitted smoking more than 10 years ago had no increased D-ROM levels compared to never smokers. There was neither a cross-sectional nor longitudinal association between any of the smoking variables and TTP levels. CONCLUSION: This large population-based cohort of older German adults suggests that smoking has long-term effects on the oxidative stress burden. The further increasing D-ROM levels of current smokers at an older age and the observation that it may take more than 10 years until the redox balance is restored are solid arguments for quitting smoking as soon as possible at any age.

A Systematic Review with Meta-Analysis Investigating the Impact of Targeted Perfusion Parameters during Extracorporeal Cardiopulmonary Resuscitation in Out-of-Hospital and Inhospital Cardiac Arrest.

Evidence regarding perfusion conditions during extracorporeal cardiopulmonary resuscitation (ECPR) is rare. Therefore, we investigated the impact of perfusion parameters on neurologic outcome and survival in patients with in- or out-of-hospital cardiac arrest (IHCA; OHCA) treated with ECPR. We performed a systematic review with meta-analysis. The focus was set on perfusion parameters and their impact on survival and a goal neurological outcome using the cerebral performance category score of 1-2. We conducted random- and mixed-effects meta-analyses and computed pooled estimates and 95% confidence intervals (CI). We included a total of n = 1,282 ECPR (100%) patients from 20 ECPR studies. The target values of flow and mean arterial pressure (MAP) were frequently available. We transferred flow and MAP target values to high, medium, and low categories. The meta-analysis could not demonstrate a single effect of flow or MAP on outcome variables. In a second mixed-effects model, the combined occurrence of targeted flow and MAP as medium and high showed a significant effect on survival (OHCA: 52%, 95% CI: 29%, 74%; IHCA: 60%, 95% CI: 35%, 85%) and on neurological outcomes (OHCA: 53%, 95% CI: 27%, 78%; IHCA: 62%, 95% CI: 38%, 86%). Random-effects analysis showed also that IHCA led to a significant 11% (p = 0.006; 95% CI: 3%, 18%) improvement in survival and 12% (p = .005; 95% CI: 4%, 21%) improvement in neurological outcomes compared to OHCA. A combination of medium flow and high MAP showed advantages in survival and for neurological outcomes. We also identified improved outcomes for IHCA.

Detraining Effects on Musculoskeletal Parameters in Early Postmenopausal Osteopenic Women: 3-Month Follow-Up of the Randomized Controlled ACTLIFE Study.

Periods of absence from supervised group exercise while maintaining physical activity might be a frequent pattern in adults' exercise habits. The aim of the present study was to determine detraining effects on musculoskeletal outcomes after a 3-month detraining period in early post-menopausal, osteopenic women. Due to the COVID-19 pandemic, we terminated the 18-month randomized controlled ACTLIFE exercise intervention immediately after the 13-month follow-up assessment. This put an abrupt stop to the high-intensity aerobic and resistance group exercise sessions undertaken three times per week by the exercise group (EG: n = 27) and the gentle exercise program performed once per week for the attention control group (CG: n = 27); but both groups were permitted to conduct individual outdoor activity for the 3-month lock-down period. Study endpoints were lean body mass (LBM), bone mineral density (BMD) at the lumbar spine (LS), maximum hip-/leg extension strength and power. Detraining-induced reductions of LBM, hip/leg strength and power (but not BMD-LS) were significantly greater (p < 0.001 to p = 0.044) compared with the CG. Significant exercise effects, i.e. differences between EG and CG, present after 13 months of exercise, were lost after 3 months of detraining for LBM (p = 0.157) and BMD-LS (p = 0.065), but not for strength (p < 0.001) and power (p < 0.001). Of note, self-reported individual outdoor activities and exercise increased by about 40% in both groups during the lock-down period. Three months' absence from a supervised group exercise protocol resulted in considerable detraining effects for musculoskeletal parameters. Thus, exercise programs for adults should be continuous rather than intermittent.Trial registration number: ClinicalTrials.gov: NCT04420806, 06.05.2020.

Effects of Different Types of Exercise on Bone Mineral Density in Postmenopausal Women: A Systematic Review and Meta-analysis.

In this sub-analysis of a comprehensive meta-analysis, we aimed to determine the effect of different types of exercise on (areal) bone mineral density (BMD) in postmenopausal women. A systematic review of the literature according to the PRISMA statement included (a) controlled trials, (b) with at least one exercise and one control group, (c) intervention ≥ 6 months, (d) BMD assessments at lumbar spine (LS), femoral neck (FN) or total hip (TH), (e) in postmenopausal women. Eight electronic databases were scanned without language restrictions up to March 2019. The present subgroup analysis was conducted as a mixed-effect meta-analysis with "type of exercise" as the moderator. The 84 eligible exercise groups were classified into (a) weight bearing (WB, n = 30) exercise, (b) (dynamic) resistance exercise (DRT, n = 18), (c) mixed WB&DRT interventions (n = 36). Outcome measures were standardized mean differences (SMD) for BMD-changes at LS, FN and TH. All types of exercise significantly affect BMD at LS, FN and TH. SMD for LS average 0.40 (95% CI 0.15-0.65) for DRT, SMD 0.26 (0.03-0.49) for WB and SMD 0.42 (0.23-0.61) for WB&DRT. SMD for FN were 0.27 (0.09-0.45) for DRT, 0.37 (0.12-0.62) for WB and 0.35 (0.19-0.51) for WB&DRT. Lastly, SMD for TH changes were 0.51 (0.28-0.74) for DRT, 0.40 (0.21-0.58) for WB and 0.34 (0.14-0.53) for WB&DRT. In summary, we provided further evidence for the favorable effect of exercise on BMD largely independent of the type of exercise. However, in order to generate dedicated exercise recommendations or exercise guideline, meta-analyses might be a too rough tool.

Duplex Shiny app quantification of the sepsis biomarkers C-reactive protein and interleukin-6 in a fast quantum dot labeled lateral flow assay.

Fast point-of-care (POC) diagnostics represent an unmet medical need and include applications such as lateral flow assays (LFAs) for the diagnosis of sepsis and consequences of cytokine storms and for the treatment of COVID-19 and other systemic, inflammatory events not caused by infection. Because of the complex pathophysiology of sepsis, multiple biomarkers must be analyzed to compensate for the low sensitivity and specificity of single biomarker targets. Conventional LFAs, such as gold nanoparticle dyed assays, are limited to approximately five targets-the maximum number of test lines on an assay. To increase the information obtainable from each test line, we combined green and red emitting quantum dots (QDs) as labels for C-reactive protein (CRP) and interleukin-6 (IL-6) antibodies in an optical duplex immunoassay. CdSe-QDs with sharp and tunable emission bands were used to simultaneously quantify CRP and IL-6 in a single test line, by using a single UV-light source and two suitable emission filters for readout through a widely available BioImager device. For image and data processing, a customized software tool, the MultiFlow-Shiny app was used to accelerate and simplify the readout process. The app software provides advanced tools for image processing, including assisted extraction of line intensities, advanced background correction and an easy workflow for creation and handling of experimental data in quantitative LFAs. The results generated with our MultiFlow-Shiny app were superior to those generated with the popular software ImageJ and resulted in lower detection limits. Our assay is applicable for detecting clinically relevant ranges of both target proteins and therefore may serve as a powerful tool for POC diagnosis of inflammation and infectious events.

Metabolite Patterns in Human Myeloid Hematopoiesis Result from Lineage-Dependent Active Metabolic Pathways.

Assessment of hematotoxicity from environmental or xenobiotic compounds is of notable interest and is frequently assessed via the colony forming unit (CFU) assay. Identification of the mode of action of single compounds is of further interest, as this often enables transfer of results across different tissues and compounds. Metabolomics displays one promising approach for such identification, nevertheless, suitability with current protocols is restricted. Here, we combined a hematopoietic stem and progenitor cell (HSPC) expansion approach with distinct lineage differentiations, resulting in formation of erythrocytes, dendritic cells and neutrophils. We examined the unique combination of pathway activity in glycolysis, glutaminolysis, polyamine synthesis, fatty acid oxidation and synthesis, as well as glycerophospholipid and sphingolipid metabolism. We further assessed their interconnections and essentialness for each lineage formation. By this, we provide further insights into active metabolic pathways during the differentiation of HSPC into different lineages, enabling profound understanding of possible metabolic changes in each lineage caused by exogenous compounds.

[Stay at Work - Feasibility and Acceptance of a Part-Time Medical Rehabilitation]. / Stay at Work ­ Machbarkeit und Akzeptanz einer berufsbegleitenden Form der medizinischen Rehabilitation.

PURPOSE: Back pain is associated with significant impairments of participation, which should be prevented by medical rehabilitation programs. The existing evidence shows that the German rehabilitation model is not effective for all target groups. In addition to intensified measures for patients with a high risk of failed return to work, a less intense rehabilitation form could be useful for patients with moderate disabilities. Therefore, in this study the feasibility of a part-time medical rehabilitation (German abbreviation: BbR) was examined. The BbR was designed as a closed group program with a therapy duration of 48 hours (2 appointments per week over 12 weeks). Furthermore, different access paths to BbR as well as the effects were focused. METHODS: Twelve groups with 6 to 12 participants each were planned in 3 outpatient rehabilitation centers. In addition to the regular application process, insured persons were recruited via the network of rehabilitation centers as well as the company service of the German Pension Insurance. The BbR focused on employed patients who were not on sick-leave and had the need for rehabilitation due to back pain. The evaluation was multi-perspective and multi-methodical. All participants completed questionnaires at admission, while and at discharge of the BbR. In addition, discussions in groups were conducted with representatives of the rehabilitation centers, the pension insurance and employers. RESULTS: In total, 7 groups with 56 participants could be realized in 2 rehabilitation centers. The typical BbR-participant was female, married, without children, 48 years old and working full for medium-sizes enterprise without shift work. The majority had no or minor no time of sick-leave in the year prior to rehabilitation. 59% of them were recruited by the rehabilitation centers; only few persons were assigned by the pension insurance. Two thirds would not have applied for a medical rehabilitation without the offer of BbR. Overall, the participants were very satisfied with the BbR. However, the compatibility of the BbR with the job and everyday life was perceived as a challenge. A pre-post comparison showed moderate to strong differences in self-rated health, pain, functional status and work ability. CONCLUSION: The BbR seems to be a useful additional concept in the German rehabilitation system for patients with moderate disabilities. Before dissemination, the identified challenges should be solved. This applies in particular to the recruitment and compatibility of rehabilitation with work and everyday life.

First Results from a Screening of 300 Naturally Occurring Compounds: 4,6-dibromo-2-(2',4'-dibromophenoxy)phenol, 4,5,6-tribromo-2-(2',4'-dibromophenoxy)phenol, and 5-epi-nakijinone Q as Substances with the Potential for Anticancer Therapy.

There is a variety of antineoplastic drugs that are based on natural compounds from ecological niches with high evolutionary pressure. We used two cell lines (Jurkat J16 and Ramos) in a screening to assess 300 different naturally occurring compounds with regard to their antineoplastic activity. The results of the compounds 4,6-dibromo-2-(2',4'-dibromophenoxy)phenol (P01F03), 4,5,6-tribromo-2-(2',4'-dibromophenoxy)phenol (P01F08), and 5-epi-nakijinone Q (P03F03) prompted us to perform further research. Using viability and apoptosis assays on the cell lines of primary human leukemic and normal hematopoietic cells, we found that P01F08 induced apoptosis in the cell lines at IC50 values between 1.61 and 2.95 µM after 72 h. IC50 values of peripheral blood mononuclear cells (PBMNCs) from healthy donors were higher, demonstrating that the cytotoxicity in the cell lines reached 50%, while normal PBMNCs were hardly affected. The colony-forming unit assay showed that the hematopoietic progenitor cells were not significantly affected in their growth by P01F08 at a concentration of 3 µM. P01F08 showed a 3.2-fold lower IC50 value in primary leukemic cells [acute myeloid leukemia (AML)] compared to the PBMNC of healthy donors. We could confirm the antineoplastic effect of 5-epi-nakijinone Q (P03F03) on the cell lines via the induction of apoptosis but noted a similarly strong cytotoxic effect on normal PBMNCs.

A smartphone readout system for gold nanoparticle-based lateral flow assays: application to monitoring of digoxigenin.

For modern approaches in precision medicine, fast and easy-to-use point-of-care diagnostics (POCs) are essential. Digoxin was chosen as an example of a drug requiring close monitoring. Digoxin is a cardiac glycoside used for the treatment of tachycardia with a narrow therapeutic window of 0.5-2.0 ng·mL-1, and toxic effects are common for concentrations above 2.5 ng·mL-1. For monitoring of blood concentration levels and treatment of intoxication, highly selective antibodies for digoxin and its hapten, digoxigenin, are available. A smartphone readout system is described for measuring digoxigenin in human serum using a common gold nanoparticle lateral flow assay (LFA). The R-package GNSplex, which also includes a Shiny app for quantitative test interpretation based on linear models, is used for image analysis. Images of lateral flow strips were taken with an iPhone camera and a simple darkbox made from black cardboard. Sensitivity and accuracy of the quantitative smartphone system as well as analytical parameters such as limit of detection (LOD) were determined and compared to data obtained with a high resolution BioImager. The data show that the smartphone based digoxin assay yields reliable quantitative results within the clinically relevant concentration range. Graphical abstract For therapeutic drug monitoring and point of care diagnostics we introduce the open source R-package GNSplex for smartphone readout and interpretation of lateral flow assays. The cardiac glycoside dixogin was used as target for this quantitative smartphone reader.

Effects of Combined Whole-Body Electromyostimulation and Protein Supplementation on Local and Overall Muscle/Fat Distribution in Older Men with Sarcopenic Obesity: The Randomized Controlled Franconia Sarcopenic Obesity (FranSO) Study.

The primary aim of the project was to determine the combined effect of whole-body electromyostimulation (WB-EMS) and protein supplements on local and overall muscle/fat distribution in older man with sarcopenic obesity (SO). Community-dwelling (cdw) men ≥ 70 years with SO were randomly allocated to a WB-EMS and protein supplementation (n = 33) or a non-intervention control group (CG: n = 34). WB-EMS was conducted 1.5 sessions of 20 min/week for 16 weeks. Whey protein supplementation aimed to ensure a daily intake of 1.8 g/kg body mass. The primary study endpoint was muscle/fat distribution of the total intra-fascial volume of the mid-thigh as determined by MRI. The core secondary endpoint was appendicular muscle mass (ASMM) and trunk fat; subordinate secondary endpoint was lower-leg performance. Thigh lean muscle volume increased significantly in the WB-EMS&P (p < 0.001) and increased slightly in the CG (p = 0.435). In parallel, fat volume increased significantly in the CG (p < 0.001) and was maintained in the WB-EMS&P group (p = 0.728). Group differences for both parameters were significant (p = 0.033 and p = 0.002). ASMM and trunk fat also differed significantly (p < 0.001) between WB-EMS and CG, with significant positive changes in the WB-EMS&P (p < 0.001) and no relevant changes in the CG (p ≥ 0.458). Finally, changes of gait velocity, leg-extensor strength, and advanced lower extremity function of the WB-EMS&P group differed significantly from the CG (p ≤ 0.002). WB-EMS combined with whey protein supplements favorably affects local and overall muscle/fat distribution and lower limb functioning in cdw men 70+ with SO. Thus, this time-saving, joint-friendly, and highly customizable approach may be an option for people either unable or unmotivated to conduct intense (resistance) exercise protocols.Trial registration number NCT02857660 on http://www.clinicaltrials.gov .

Effect of whole-body electromyostimulation and / or protein supplementation on obesity and cardiometabolic risk in older men with sarcopenic obesity: the randomized controlled FranSO trial.

BACKGROUND: Sarcopenic Obesity (SO) is characterized by low lean and high fat mass; i.e. from a functional aspect a disproportion between engine (muscle) and mass to be moved (fat). At present, most research focuses on the engine, but the close "cross talk" between age-associated adipose and skeletal muscle tissue inflammation calls for comprehensive interventions that affect both components alike. Protein and exercise are likely candidates, however with respect to the latter, the enthusiasm for intense and frequent exercise is rather low, especially in functionally limited older people. The aim of this study was therefore to evaluate the effect of whole-body electromyostimulation (WB-EMS), a time-efficient, joint-friendly and highly customizable exercise technology, on obesity parameters and cardiometabolic risk in men with SO. METHODS: One-hundred community-dwelling (cdw) Bavarian men ≥70 years with SO were randomly assigned to either (a) whey protein supplementation (WPS), (b) WB-EMS and protein supplementation (WB-EMS&P) or (c) non-intervention control (CG). Protein supplementation contributed to an intake of 1.7-1.8 g/kg/body mass/d, WB-EMS consisted of 1.5 × 20 min/week (85 Hz, 350 µs, 4 s of strain-4 s of rest) with moderate-high intensity. Using an intention to treat approach with multiple imputation, the primary study endpoint was total body fat mass (TBF), secondary endpoints were trunk fat mass (TF), waist circumference (WC) and total-cholesterol/HDL-cholesterol ratio (TC/HDL-C). RESULTS: After 16 weeks of intervention, TBF was reduced significantly in the WPS (- 3.6 ± 7.2%; p = 0.005) and WB-EMS&P (- 6.7 ± 6.2%; p < 0.001), but not in the CG (+ 1.6 ± 7.1%; p = 0.191). Changes in the WB-EMS&P (p < 0.001) and the WPS group (p = 0.011) differ significantly from the CG. TF decreased in the WB-EMS&P (p < 0.001) and WPS (p = .117) and increased in the CG (p = .159); WC decreased significantly in the treatment groups and was maintained in the CG. Lastly, the TC/HDL-C ratio improved significantly in the WB-EMS&P and WPS group and was maintained in the CG. Significant differences between WB-EMS&P and WPS were determined for waist circumference only (p = 0.015; TBF: p = 0.073; TF: p = 0.087; TC/HDL-C: p = .773). CONCLUSION: Moderate-high dosed whey protein supplementation, especially when combined with WB-EMS, may be a feasible choice to address obesity and cardiometabolic risk in older cdw men with SO unable or unmotivated to exercise conventionally. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02857660 ; registration date: 05/01/2017.